External validity of randomized controlled trials on Alzheimer's disease: the biases of frailty and biological aging

To date, the external validity of randomized controlled trials (RCTs) on Alzheimer's disease (AD) has been assessed only considering monodimensional variables. Nevertheless, looking at isolated and single characteristics cannot guarantee a sufficient level of appreciation of the AD patients' complexity. The only way to understand whether the two worlds (i.e., research and clinics) deal with the same type of patients is to adopt multidimensional approaches more holistically reflecting the biological age of the individual. In the present study, we compared measures of frailty/biological aging [assessed by a Frailty Index (FI)] of a sample of patients with AD resulted eligible and subsequently included in phase III RCTs compared to patients referring to the same clinical service, but not considered for inclusion. The "RCT sample" and the "real world sample" were found to be statistically similar for all the considered sociodemographic and clinical variables. Nevertheless, the "real world sample" was found to be significantly frailer compared to the "RCT sample," as indicated by higher FI scores [0.28 (SD 0.1) vs. 0.17 (SD 0.1);p < 0.001, respectively]. Moreover, when assessing the relationship between FI and age, we found that the correlation was almost null in the "RCT sample" (Spearman'sr = 0.01;p = 0.98), while it was statistically significant in the "real world sample" (r = 0.49;p = 0.02). The application of too rigid designs may result in the poor representativeness of RCT samples. It may even imply the study of a condition biologically different from that observed in the "real world." The adoption of multidimensional measures capable to capture the individual's biological age may facilitate evaluating the external validity of clinical studies, implicitly improving the interpretation of the results and their translation in the clinical arena

Nutrition and dementia: Evidence for preventive approaches?

In recent years, the possibility of favorably influencing the cognitive trajectory through promotion of lifestyle modifications has been increasingly investigated. In particular, the relationship between nutritional habits and cognitive health has attracted special attention. The present review is designed to retrieve and discuss recent evidence (published over the last 3 years) coming from randomized controlled trials (RCTs) investigating the efficacy of nutritional interventions aimed at improving cognitive functioning and/or preventing cognitive decline in non-demented older individuals. A systematic review of literature was conducted, leading to the identification of 11 studies of interest. Overall, most of the nutritional interventions tested by the selected RCTs were found to produce statistically significant cognitive benefits (defined as improved neuropsychological test scores). Nevertheless, the clinical meaningfulness of such findings was not adequately discussed and appears controversial. In parallel, only 2 studies investigated between-group differences concerning incident dementia and mild cognitive impairment cases, reporting conflicting results. Results of the present review suggest that several dietary patterns and nutritional components may constitute promising strategies in postponing, slowing, and preventing cognitive decline. However, supporting evidence is overall weak and further studies are needed

Geriatric medicine and health care system: how can they fit together?

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Geriatric syndromes: How to treat

The survival of HIV-infected persons has been increasing over the last years, thanks to the implementation of more effective pharmacological and non-pharmacological interventions. Nevertheless, HIV-infected persons are often \u201cbiologically\u201d older than their \u201cchronological\u201d age due to multiple clinical, social, and behavioral conditions of risk. The detection in this population of specific biological features and syndromic conditions typical of advanced age has made the HIV infection an interesting research model of accelerated and accentuated aging. Given such commonalities, it is possible that \u201cbiologically aged\u201d HIV-positive persons might benefit from models of adapted and integrated care developed over the years by geriatricians for the management of their frail and complex patients. In this article, possible strategies to face the increasingly prevalent geriatric syndromes in HIV-infected persons are discussed. In particular, it is explained the importance of shifting from the traditional disease-oriented approach into models of care facilitating a multidisciplinary management of frailty

An exploration on whole-body and foot-based vibrotactile sensitivity to melodic consonance

Consonance is a distinctive attribute of musical sounds, for which a psychophysical explanation has been found leading to the critical band perceptual model. Recently this model has been hypothesized to play a role also during tactile perception. In this paper the sensitivity to vibrotactile consonance was subjectively tested in musicians and non-musicians. Before the test, both such groups listened to twelve melodic intervals played with a bass guitar. After being acoustically isolated, participants were exposed to the same intervals in the form of either a whole-body or foot-based vibrotactile stimulus. On each trial they had to identify whether an interval was ascending, descending or unison. Musicians were additionally asked to label every interval using standard musical nomenclature. The intervals identification as well as their labeling was above chance, but became progressively more uncertain for decreasing consonance and when the stimuli were presented underfoot. Musicians\u2019 labeling of the stimuli was incorrect when dissonant vibrotactile intervals were presented underfoot. Compared to existing literature on auditory, tactile and multisensory perception, our results reinforce the idea that vibrotactile musical consonance plays a perceptual role in both musicians and non-musicians. Might this role be the result of a process occurring at central and/or peripheral level, involving or not activation of the auditory cortex, concurrent reception from selective somatosensory channels, correlation with residual auditory information reaching the basilar membrane through bone conduction, is a question our preliminary exploration leaves open to further research work

Shipping and Air Quality in Italian Port Cities: State-of-the-Art Analysis of Available Results of Estimated Impacts

Populated coastal areas are exposed to emissions from harbour-related activities (ship traffic, loading/unloading, and internal vehicular traffic), posing public health issues and environmental pressures on climate. Due to the strategic geographical position of Italy and the high number of ports along coastlines, an increasing concern about maritime emissions from Italian harbours has been made explicit in the EU and IMO (International Maritime Organization, London, UK) agenda, also supporting the inclusion in a potential Mediterranean emission control area (MedECA). This work reviews the main available outcomes concerning shipping (and harbours') contributions to local air quality, particularly in terms of concentration of particulate matter (PM) and gaseous pollutants (mainly nitrogen and sulphur oxides), in the main Italian hubs. Maritime emissions from literature and disaggregated emission inventories are discussed. Furthermore, estimated impacts to air quality, obtained with dispersion and receptor modeling approaches, which are the most commonly applied methodologies, are discussed. Results show a certain variability that suggests the necessity of harmonization among methods and input data in order to compare results. The analysis gives a picture of the effects of this pollution source, which could be useful for implementing effective mitigation strategies at a national level

CDK12/13 promote splicing of proximal introns by enhancing the interaction between RNA polymerase II and the splicing factor SF3B1

Transcription-associated cyclin-dependent kinases (CDKs) regulate the transcription cycle through sequential phosphorylation of RNA polymerase II (RNAPII). Herein, we report that dual inhibition of the highly homologous CDK12 and CDK13 impairs splicing of a subset of promoter-proximal introns characterized by weak 3 ' splice sites located at larger distance from the branchpoint. Nascent transcript analysis indicated that these introns are selectively retained upon pharmacological inhibition of CDK12/13 with respect to downstream introns of the same pre-mRNAs. Retention of these introns was also triggered by pladienolide B (PdB), an inhibitor of the U2 small nucelar ribonucleoprotein (snRNP) factor SF3B1 that recognizes the branchpoint. CDK12/13 activity promotes the interaction of SF3B1 with RNAPII phosphorylated on Ser2, and disruption of this interaction by treatment with the CDK12/13 inhibitor THZ531 impairs the association of SF3B1 with chromatin and its recruitment to the 3 ' splice site of these introns. Furthermore, by using suboptimal doses of THZ531 and PdB, we describe a synergic effect of these inhibitors on intron retention, cell cycle progression and cancer cell survival. These findings uncover a mechanism by which CDK12/13 couple RNA transcription and processing, and suggest that combined inhibition of these kinases and the spliceosome represents an exploitable anticancer approach

Use of Biomarkers in Ongoing Research Protocols on Alzheimer's Disease

The present study aimed to describe and discuss the state of the art of biomarker use in ongoing Alzheimer's disease (AD) research. A review of 222 ongoing phase 1, 2, 3, and 4 protocols registered in the clinicaltrials.gov database was performed. All the trials (i) enrolling subjects with clinical disturbances and/or preclinical diagnoses falling within the AD continuum; and (ii) testing the efficacy and/or safety/tolerability of a therapeutic intervention, were analyzed. The use of biomarkers of amyloid deposition, tau pathology, and neurodegeneration among the eligibility criteria and/or study outcomes was assessed. Overall, 58.2% of ongoing interventional studies on AD adopt candidate biomarkers. They are mostly adopted by studies at the preliminary stages of the drug development process to explore the safety profile of novel therapies, and to provide evidence of target engagement and disease-modifying properties. The biologically supported selection of participants is mostly based on biomarkers of amyloid deposition, whereas the use of biomarkers as study outcomes mostly relies on markers of neurodegeneration. Biomarkers play an important role in the design and conduction of research protocols targeting AD. Nevertheless, their clinical validity, utility, and cost-effectiveness in the "real world" remain to be clarified

Experiments on the Control of Esca by Thricoderma

Trichoderma harzianum T39 (Trichodex®) and T. longibrachiatum strain 6 were applied on grapevine to determine their effectiveness against Phaeomoniella chlamydospora on vine cuttings and pruning wounds. Cuttings were dipped in a Trichoderma suspension either before or after callusing. Pre-callusing dips were carried out for 3 years and yielded contradictory results. By contrast, post-callusing Trichoderma dips led to significant growth of hairy roots and a reduction in the longitudinal discolorations caused by P. chlamydospora inoculated into the rootstock after dipping. Trichoderma spp. were also applied to pruning wounds of grafted potted vines, which were then inoculated by placing drops of a conidial suspension of P. chlamydospora on the wound surface. Trichoderma application here prevented black goo and necrosis in the wood below the wound. In the vineyard, T. harzianum T39 was sprayed after pruning for two consecutive years. The biocontrol agent was reisolated from the wood close to the sprayed pruning wounds for up to 2 months after spraying. Although further investigations are necessary, our findings suggest that Trichoderma could be one of the steps in the control of esca

Delirium and frailty in older adults: Clinical overlap and biological underpinnings

Delirium; Frailty; Hallmarks of agingDelirio; Fragilidad; Características del envejecimientoDeliri; Fragilitat; Trets distintius de l'envellimentFrailty and delirium are two common geriatric syndromes sharing several clinical characteristics, risk factors, and negative outcomes. Understanding their interdependency is crucial to identify shared mechanisms and implement initiatives to reduce the associated burden. This literature review summarizes scientific evidence on the complex interplay between frailty and delirium; clinical, epidemiological, and pathophysiological commonalities; and current knowledge gaps. We conducted a PubMed systematic search in June 2023, which yielded 118 eligible articles out of 991. The synthesis of the results-carried out by content experts-highlights overlapping risk factors, clinical phenotypes, and outcomes and explores the influence of one syndrome on the onset of the other. Common pathophysiological mechanisms identified include inflammation, neurodegeneration, metabolic insufficiency, and vascular burden. The review suggests that frailty is a risk factor for delirium, with some support for delirium associated with accelerated frailty. The proposed unifying framework supports the integration and measurement of both constructs in research and clinical practice, identifying the geroscience approach as a potential avenue to develop strategies for both conditions. In conclusion, we suggest that frailty and delirium might be alternative-sometimes coexisting-manifestations of accelerated biological aging. Clinically, the concepts addressed in this review can help approach older adults with either frailty or delirium from a different perspective. From a research standpoint, longitudinal studies are needed to explore the hypothesis that specific pathways within the biology of aging may underlie the clinical manifestations of frailty and delirium. Such research will pave the way for future understanding of other geriatric syndromes as well